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In his editorial, Eisenach 1 highlighted an interesting paradox; while attempting to produce profound analgesia with high doses of potent opioids, it is possible to produce a “preemptive hyperalgesic” effect. In the two human studies referenced, 2,3 high doses of systemic remifentanil and fentanyl produced acute hyperalgesia.

In his editorial, Bernards 5 mentions his concern that “alfentanil and sufentanil (and to some extent fentanyl)” are used in the epidural space, “…despite mounting evidence that these opioids do not produce analgesia by a selective spinal mechanism.” However, there is evidence that epidural fentanyl, when it is administered in the minimal effective dose, has a selective spinal action. 6–10

In humans, 11 lumbar cerebrospinal fluid levels of fentanyl increase rapidly after epidural fentanyl administration, and Bernards and Sorkin 12 have shown that, in pigs, “epidural fentanyl moves rapidly from the epidural space to the spinal cord.” Prolonged postoperative epidural fentanyl administration can produce plasma levels similar to those of systemic administration. 13 However, spinal cord levels of fentanyl still would be expected to be higher after epidural than after systemic administration. It is therefore surprising that the analgesic effectiveness of epidural and systemic fentanyl often are reported to be comparable, even if plasma levels are similar. This is especially so if, as suggested by Bernards, 5 there is synergy between spinal and supraspinal opioid analgesia in humans.

It may be that, by producing relatively high spinal compared with systemic levels of fentanyl, epidural fentanyl administration can induce acute selective spinal hyperalgesia. The greater the magnitude of selective spinal hyperalgesia induced, the smaller the difference in analgesic effectiveness of epidural and systemic fentanyl would be. This could help to explain why several studies have not found a difference between epidural and systemic fentanyl analgesia. Administration of epidural fentanyl in the minimal effective dose may limit the development of spinal hyperalgesia, thereby facilitating selective spinal analgesia.